title: Sleep disturbances in a neuropathic pain-like condition in the mouse are associated with altered GABAergic transmission in the cingulate cortex.
abstract: Insomnia is a common problem for people with chronic pain. Cortical GABAergic neurons are part of the neurobiological substrate that underlies homeostatic sleep regulation. In the present study, we confirmed that sciatic nerve ligation caused thermal hyperalgesia and tactile allodynia in mice. In this experimental model for neuropathic pain, we found an increase in wakefulness and a decrease in non-rapid eye movement sleep under a neuropathic pain-like state. Under these conditions, membrane-bound GABA (γ-aminobutyric acid) transporters (GATs) on activated glial fibrillary acidic protein-positive astrocytes were significantly increased in the cingulate cortex, and extracellular GABA levels in this area after depolarization were rapidly decreased by nerve injury. Furthermore, sleep disturbance induced by sciatic nerve ligation was improved by the intracingulate cortex injection of a GAT-3 inhibitor. These findings provide novel evidence that sciatic nerve ligation decreases extracellular-released GABA in the cingulate cortex of mice. These phenomena may, at least in part, explain the insomnia in patients with neuropathic pain. Neuropathic pain-like stimuli suppress the GABAergic transmission with increased GABA (γ-aminobutyric acid) transporters located on activated astrocytes in the cingulate cortex related to sleep disturbance.
authors.affiliation: Department of Toxicology, Hoshi University, School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan Laboratory of the Biology of Addictive Diseases, The Rockefeller University, 1230 York Avenue, New York City, NY 10065-6399, USA Cancer Pathophysiology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan Division of Palliative Medicine, Wakayama Medical University Hospital, 811-1 Kimiidera, Wakayama-shi, Wakayama 641-8510, Japan Department of Psychiatry, Nihon University, School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8601, Japan Palliative Care Unit, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan Department of Palliative Medicine, Palliative Care Team, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Keiichi
authors.initials: K
authors.lastname: Niikura
authors.forename: Kana
authors.initials: K
authors.lastname: Nanjo-Niikura
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.forename: Masaharu
authors.initials: M
authors.lastname: Furuya
authors.forename: Akira
authors.initials: A
authors.lastname: Yamashita
authors.forename: Mai
authors.initials: M
authors.lastname: Saeki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsushima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imai
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Shimizu
authors.forename: Megumi
authors.initials: M
authors.lastname: Asato
authors.forename: Naoko
authors.initials: N
authors.lastname: Kuzumaki
authors.forename: Daiki
authors.initials: D
authors.lastname: Okutsu
authors.forename: Kan
authors.initials: K
authors.lastname: Miyoshi
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yoshi
authors.initials: Y
authors.lastname: Tsukiyama
authors.forename: Michiko
authors.initials: M
authors.lastname: Konno
authors.forename: Kinomi
authors.initials: K
authors.lastname: Yomiya
authors.forename: Motohiro
authors.initials: M
authors.lastname: Matoba
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004576:Electromyography; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D006993:Hypnotics and Sedatives / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D017551:Microdialysis; D008874:Midazolam / Q000494:pharmacology / Q000627:therapeutic use; D009557:Nipecotic Acids / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation / Q000009:adverse effects; D011725:Pyridines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D020426:Sciatic Neuropathy / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D012893:Sleep Wake Disorders / Q000209:etiology*; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C092337:1-(2-(tris(4-methoxyphenyl)methoxy)ethyl)-3-piperidinecarboxylic acid; D000840:Anisoles; D050485:GABA Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D006993:Hypnotics and Sedatives; D009557:Nipecotic Acids; D011725:Pyridines; D012333:RNA, Messenger; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; D008874:Midazolam